Estrogens or androgens attenuate osteoclastogenesis and osteoblastogenesis, and thereby remodeling, via transcriptional regulation of genes encoding cytokines. In addition, they exert pro-apoptotic effects on osteoclasts but anti-apoptotic effects on osteoblasts and osteocytes, by a non-genotypic, yet estrogen receptor (ER) or androgen receptor (AR)- dependent mechanisms of action, which involves activation of extracellular signal regulated kinases (ERKs). Based on this evidence, it is proposed that the non-genotypic effects of estrogens are mediated by an "ERK activating domain" of the ER that resides within the ligand- bonding domain of the protein, and that the protective effects of estrogens on the adult skeleton are mediated by both genotypic and non-genotypic mechanisms of action. Loss of the non-genotypic effects could be at least partially responsible for the imbalance between formation and resorption and the progressive loss of bone mass and/or the diminished microarchitectural quality or strength in estrogen deficient states. Moreover, sex non-specific signaling by estrogens or androgens through the ER alpha or beta or the AR may account for the equivocal skeletal phenotype of the ER-deficient mice and humans. To test these hypotheses, the role of the ERs in the control of the life span of osteoblasts and osteoclasts will be sought by searching for proteins that physically interact with the "ERK-activating domain" of the ER and link it to the MAP kinase cascade, and by determining whether genotropic or non-genotropic effects of the ER are required for the prop-apoptotic effect of estrogens on osteoclasts, using ER peptide antagonists that can block completely ER action or dissociate genotropic from non-genotropic actions. The contribution of the ERS to the bone protective effects of estrogens will be examined by comparing the skeletal phenotype in wild type ovariectomized mice and mice carrying a tetracyline-inducible transgene of ER peptide antagonists (alphaII+2X293) that block the transcriptional but not the anti-apoptotic, activity of the ERS. Finally, transgenic mice with inactivated ERalpha will be generated by expressing Cre recombinase in osteoblasts or osteoblasts under the control of the tetracycline-ON system and crossing with mice in which exon 3 of the ERalpha allele will be floxed with two loxP sites.